Nilsson Daniel, Heglind Mikael, Arani Zahra, Enerbäck Sven
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Physiol Rep. 2019 May;7(9):e14083. doi: 10.14814/phy2.14083.
Foxc2 is one of the earliest podocyte markers during glomerular development. To circumvent embryonic lethal effects of global deletion of Foxc2, and to specifically investigate the role of Foxc2 in podocytes, we generated mice with a podocyte-specific Foxc2 deletion. Mice carrying the homozygous deletion developed early proteinuria which progressed rapidly into end stage kidney failure and death around postnatal day 10. Conditional loss of Foxc2 in podocytes caused typical characteristics of podocyte injury, such as podocyte foot process effacement and podocyte microvillus transformation, probably caused by disruption of the slit diaphragm. These effects were accompanied by a redistribution of several proteins known to be necessary for correct podocyte structure. One target gene that showed reduced glomerular expression was Nrp1, the gene encoding neuropilin 1, a protein that has been linked to diabetic nephropathy and proteinuria. We could show that NRP1 was regulated by Foxc2 in vitro, but podocyte-specific ablation of Nrp1 in mice did not generate any phenotype in terms of proteinuria, suggesting that the gene might have more important roles in endothelial cells than in podocytes. Taken together, this study highlights a critical role for Foxc2 as an important gene for podocyte function.
Foxc2是肾小球发育过程中最早出现的足细胞标志物之一。为了规避Foxc2整体缺失的胚胎致死效应，并专门研究Foxc2在足细胞中的作用，我们构建了足细胞特异性缺失Foxc2的小鼠。携带纯合缺失的小鼠出现早期蛋白尿，并迅速发展为终末期肾衰竭，在出生后第10天左右死亡。足细胞中Foxc2的条件性缺失导致了足细胞损伤的典型特征，如足细胞足突消失和足细胞微绒毛转化，这可能是由裂孔隔膜破坏引起的。这些效应伴随着几种已知对正确足细胞结构至关重要的蛋白质的重新分布。一个肾小球表达降低的靶基因是Nrp1，即编码神经纤毛蛋白1的基因，该蛋白与糖尿病肾病和蛋白尿有关。我们可以证明，NRP1在体外受Foxc2调控，但小鼠足细胞特异性敲除Nrp1并未产生任何蛋白尿相关表型，这表明该基因在内皮细胞中的作用可能比在足细胞中更重要。综上所述，本研究强调了Foxc2作为足细胞功能重要基因的关键作用。
